Throughout this application various patents and publications are referenced and citations are provided in parentheses. The disclosure of these patents and publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
The presence of microorganisms is associated with gingivitis, periodontal disease, and dental plaque. That microorganisms are a causative element of, or are associated with, dental and other diseases is the underlying principle of many studies (See e.g., Ericsson, Y., Acta Pathol Microbiol. Scandinav., 35: 573-583 (Fasc 6), (1954); Ericsson, Y., and Lundbeck, H., Acta Pathol Microbiol. Scandinav., 37: 493-506 (Fasc. 6), (1955); Ericsson, Y., Lundbeck, H., Acta Pathol. Microbiol. Scandinav., 37: 507-526 (Fasc 6), (1955); Kristoffersen, T., Odont. Tid., 71: 179-198, (1963); and Johansen, J. R., Flotra, L., and Gjermo, P., Acta Odontol. Scandinav., 28: (5) 661-677, (1970)).
Studies have shown that copper ion has a catalytic effect on the oxidation of ascorbic acid (See, e.g., Ball, E. G., J. Biol. Chem , 118: 219-239, at 223 citing references, (1937); Barron, E.S.G., DeMeio, R. H., and Klemperer, F., J. Biol. Chem., 112: 625-640, (1936); Mystkowski, E. M., Biochem. J., 36: 494-500 (1942)).
Studies have also shown that the oxidation of ascorbic acid in the presence of the copper ion catalyst has antimicrobial effects, and that copper ion greatly enhanced those effects. (Ericsson, Y., Lundbeck, H., Acta Pathol. Microbiol. Scandinav., 37: 493-506 (Fasc. 6), (1955); Kristoffersen, T., Odont. Tid., 71: 179-198, 180 and citations therein, (1963)). In other words, these studies showed that copper ion has a synergistic effect on the antimicrobial properties of the ascorbic acid oxidation reaction.
Ericsson, S. Y., et al., U.S. Pat. No. 3,065,139 (1962), disclose an anti-infectant or antimicrobial composition that was clinically tested for gingivitis and stomatitis. The composition comprises an enediol compound such as ascorbic acid, an added oxidizing agent such as sodium percarbonate, and a catalyst such as copper ion. The patent discloses that the invention is in the form of a water-free powder, tablet, or paste, which at time of application is dissolved or suspend in water, making an aqueous solution Thus, upon application, the composition is in a water solution Ericsson et al. disclose that a clinically useful solution may at the moment of application contain about 1.76 mg/ml to 7.04 mg/ml ascorbic acid (or 0.01 to 0.04 molar concentration); 1 mg/ml to 5 mg/ml sodium percarbonate (or 0.1 to 0.5 weight percent); and about 0.008 mg/ml copper sulfate (or 0.0008 weight percent). Ericsson et al. disclose that the reaction is very rapid once the ingredients are in presence of water, with the antimicrobial action being valid for a reaction time of only five minutes.
Unlike the composition of U.S. Pat. No. 3,065,139, the gel composition of the present invention involves the use of a gel carrier, does not require an added oxidizing agent, and provides antimicrobial action effective for at least thirty minutes. Moreover, because of the gel carrier, the ascorbic acid and copper ion can be targeted to desired or affected areas of the oral cavity, and when released from the gel, the ascorbic acid and copper remain bound or stuck to the tooth surface. U.S. Pat. No. 3,065,139 does not disclose an unexpected improvement in the prevention or treatment of gingivitis, periodontal disease, or dental plaque by using a gel composition comprising ascorbic acid and copper ion.
Taylor, R., U.S. Pat. No. 2,470,906 (1949), discloses a composition useful for the cleansing of teeth, gums, tongue, and other parts of the oral cavity. The composition comprises ascorbic acid or its acid analogues in a liquid, paste, or powder form. The patent does not disclose or suggest the use of copper ion, a gel carrier, or use of the composition for the prevention or treatment of gingivitis, periodontal disease, and dental plaque.
Evers et al., U.S. Pat. No. 3,886,265 (1975), disclose a composition effective for bad breath. The composition comprises an enediol compound having at most six carbon atoms such as ascorbic acid, and a peroxide oxidizing agent. The patent does not disclose or suggest the use of copper ion, a gel carrier, or the use of the composition for the prevention or treatment of gingivitis, periodontal disease, or dental plaque. Also, the present invention contains no added oxidizing agent.
Hofmann et al., U.S. Pat. No. 3,992,519 (1976), disclose a composition in toothpaste, mouthwash, or chewing gum form comprising an antibacterial compound, a vitamin, and a surfactant, useful in the prophylaxis and treatment of inflammatory diseases of the periodontium such as gingivitis and periodontitis. The antibacterial component of the patent comprises one or more pharmaceutically acceptable esters of p-hydroxybenzoic acid and or one or more pharmaceutically acceptable esters of o-hydroxybenzoic acid. The vitamin component of the patent comprises one or more of the following: aescin, rutin, panthenol, nicotinamide and vitamin E, and may further comprise small amounts of other vitamins such as vitamin C, vitamin K, and B group vitamins. The surfactant component of the patent comprises one or more anionic surfactants from examples of a listed group, or cationic surfactants. The patent does not disclose or suggest the use of copper ion or a gel carrier. Moreover, although the composition may further comprise small amounts of vitamins such as vitamin C (ascorbic acid), Hofmann et al. do not disclose or suggest the use of vitamin C (ascorbic acid) as the primary vitamin component. Furthermore, the present invention does not require the use of either a surfactant or an added antibacterial component.
Two commercial products containing ascorbic acid, sodium percarbonate, and copper sulfate have been produced The first product appeared under the trade name Ascoxal .RTM., or Gum-Ox .RTM.; and the second commercial product appeared under the trade name Ascoxal T .RTM.. The manufacturer suggested that Ascoxal .RTM. would be helpful in the treatment of stomatitis, gingivitis, and oral mycotic and coli-infections, among other uses. (Kristoffersen, T., Odont. Tid., 71: 179-198, 181, (1963)).
The compositions of Ascoxal .RTM. and Ascoxal T .RTM. are similar to that disclosed in U.S. Pat. No. 3,065,139, containing ascorbic acid, copper sulfate, and sodium percarbonate. Ascoxal .RTM. contains 100 mg ascorbic acid, 70 mg sodium percarbonate, and 0.2 mg copper sulfate in tablet form, which is dissolved in 25 ml of water to provide a water solution taken as a mouthwash. (Johansen, J. R., Flotra, L., Gjermo, P., Acta Odontol. Scandinav., 28: (5) 661-677, 661-662 (1970). The resulting concentrations of ascorbic acid, copper sulfate, and sodium percarbonate of the Ascoxal .RTM. mouthwash are approximately the same concentrations as disclosed by Ericsson in U.S. Pat. No. 3,065,139, and in Ericsson, Y., Acta Pathol. Microbiol. Scandinav , 35: 573-583 (Fasc. 6), (1954). Ascoxal T .RTM. is in the form of a chewable tablet, containing a higher local concentration of the active components of the same ingredients present in the Ascoxal .RTM. product. (Johansen, J. R., Flotra, L., and Gjermo, P., Acta Odontol. Scandinav., 28: (5) 661-677, 662, (1970)).
In contrast to Ascoxal .RTM. and Ascoxal T .RTM., the present invention is in the form of a gel. Because the compositions of Ascoxal .RTM. and Ascoxal T .RTM. correspond to that described in U.S. Pat. No. 3,065,139, the oxidation reaction of ascorbic acid takes place within a short time after the ingredients are in the presence of water, with the antimicrobial action being valid for a time of only five minutes. The reaction in the present invention, however, is effective for at least thirty minutes. Furthermore, the present invention is designed to allow targeting to desired areas of the oral cavity. Another difference is that the composition of the Ascoxal .RTM. and Ascoxal T .RTM. products include sodium percarbonate as an oxidizing agent, whereas the present invention has no added oxidizing agent.
Researchers have clinically tested the Ascoxal .RTM. mouthwash and the Ascoxal T .RTM. chewable tablet products for their effectiveness in treating gingivitis and the prevention of plaque. Conflicting results were obtained. (Cf. Kristoffersen, T., Odont. Tid., 71: 179-198, (1963) (finding no statistically significant effect on Ascoxal .RTM. use in rate and degree of plaque and calculus formation); Muller, E., Schroeder, H. E., and Muhlemann, H. R., Helv. Odont. Acta, 6: 42-45, 44 (1962) (finding that Ascoxal .RTM. had marked inhibitory effect on early calculus formation)).
In a later study, Johansen et al. clinically evaluated Ascoxal T .RTM. for its effect on plaque formation and gingivitis. (Johansen, J. R., Flotra, L., and Gjermo, P., Acta Odontol. Scandinav., 28: (5) 661-677, (1970)). Johansen et al. explained that the purpose of their study was to clarify the effects of Ascoxal T .RTM. on plaque formation and gingivitis, noting conflicting results of previous investigations examining the use of Ascoxal .RTM.. (Johansen, J. R., Flotra, L., and Gjermo, P., Acta Odontol. Scandinav., 28: (5) 661-677, 662 and citations therein, (1970)). In their study, Johansen et al. found no statistically significant effect on the progression of experimental gingivitis, and with regard to plaque formation, their results were inconclusive. (Johansen, J. R., Flotra, L., and Gjermo, P., Acta Odontol. Scandinav., 28: (5) 661-677, (1970)).
The present invention reveals a gel composition containing ascorbic acid and copper ion that optimizes the antimicrobial effect for the prevention or treatment of gingivitis, periodontal disease, and dental plaque. This invention differs from the prior art in three ways. First, the present invention requires that the ascorbic acid and copper ion be inside a gel carrier. In contrast, the prior art does not disclose or suggest a gel carrier. Secondly, in this invention the reaction between ascorbic acid and copper ion, upon application, will remain effective for at least thirty minutes. In contrast, the prior art, especially U.S. Pat. No. 3,065,139, and Ascoxal .RTM. and the Ascoxal T .RTM. which have compositions similar to U.S. Pat. No. 3,065,139, does not suggest that the reaction will be effective for at least thirty minutes. Thirdly, this invention requires the addition of no oxidizing agent. In contrast, U.S. Pat. No. 3,065,139, Ascoxal .RTM., and Ascoxal T .RTM. require the addition of an oxidizing agent, such as sodium percarbonate.
The gel composition of the present invention has important advantages over liquid, chewable tablet, or paste forms. One important advantage is the property of substantivity. Substantivity relates to the ability to bind or stick to a surface. Specifically, substantivity here relates the ability of the ascorbic acid and copper ion to bind or stick to the tooth surface, upon release from the gel composition upon application within the oral cavity of a subject. Substantivity is important because it allows for longer contact of the ascorbic acid and copper ion with the tooth surface. The result is enhancement of the antimicrobial effect against the significant oral microorganisms that are causative agents of, or associated with, various dental diseases, including gingivitis, periodontal disease, and dental plaque.
Experiments using atomic absorption showed that application of the gel composition to enamel leaves the copper ion stuck or bound to the enamel surface where the gel was applied. Although the amount of ascorbic acid remaining stuck or bound to the tooth surface when released from the gel composition was not measured, it is believed that the ascorbic acid likewise remains stuck or bound to the tooth surface as well.
In contrast, experiments using atomic absorption showed that when the ascorbic acid and copper ion are delivered in aqueous form, as in a mouthwash, there is substantially less sticking or binding of copper ion to the tooth surface. In other words, the gel composition of this invention increases the contact time of the copper ion, and presumably the ascorbic acid, with tooth surfaces.
In practice, upon application of the gel composition, the patient is instructed not to rinse the mouth until about thirty minutes after application of the gel composition The antimicrobial activity continues throughout this thirty minute period, for Barron, et al. noted that in experiments involving an aqueous solution of 0.02 mM of ascorbic acid in phosphate buffer plus 0.1 molar NaCl, with 0.0002 mM of copper chloride as catalyst, with final pH of 6.00, half of the ascorbic acid was oxidized in 16.2 minutes; and that without NaCl, ascorbic acid was half oxidized in 15 minutes. (Barron, E.S.G., DeMeio, R. H., and Klemperer, F., J. Biol. Chem., 112: 625-640, 639 (1936).
The gel also allows for targeting of the ascorbic acid and copper ion to desired areas of the oral cavity Targeting is especially useful for treatment purposes, allowing the gel to be applied to affected areas. The targeting and substantivity properties of the gel thus allow for application to desired areas of the oral cavity, and prolonged contact of the ascorbic acid and copper ion to exert the antimicrobial effect. In contrast, mouthwashes or chewable tablets allow for only momentary contact of the ascorbic acid and copper ion with teeth, and do not practically allow for targeting. This invention significantly overcomes those problems.
Another important feature of this invention is non-toxicity. This invention is to be applied to tooth or gum surfaces within the oral cavity of a subject for the prevention or treatment of gingivitis, periodontal disease, and dental plaque. This invention involves the application of non-toxic agents. Since the diseases are chronic in nature, treatment might cover long periods of times, ranging from days, months, to years. The active agents, namely ascorbic acid and copper ion, are vitamins and minerals.
In contrast, the presence of sodium percarbonate in the composition described in U.S. Pat. No. 3,065,139, which in turn is similar to the compositions of Ascoxal .RTM., and Ascoxal T .RTM., leads to questions of safety. In that regard, Muller et al., in a clinical evaluation finding that Ascoxal .RTM. had a marked inhibitory effect on early calculus formation, noted that the inhibitory data observed with Ascoxal .RTM. rinsing are only of theoretical interest, saying that adverse effects on the oral flora and mucosa are possible after its use for years as an oral antiseptic. (Muller, E., Schroeder, H. E., and Muhlemann, H. R., Helv. Odont. Acta, 6: 42-45, 44 (1962). Ericsson, in a study involving a composition similar to the one described in U.S. Pat. No. 3,065,139, Ascoxal .RTM., and Ascoxal T .RTM., said that the possibility of local or general effects attending the application of ascorbic acid with an oxidizing agent to the mucous membranes of the body should not be disregarded, calling for careful study. (Ericsson, Y., Acta Pathol. Microbiol. Scandinav., 35: 573-583, 582 (1954).